Comparison of TP53 Mutations in Myelodysplasia and Acute Leukemia Suggests Divergent Roles in Initiation and Progression

TP53 mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations impact disease biology, and whether they differ between disease categories, remain unknown. We analyzed TP53 mutations in four myeloid neoplasm subtypes (MDS, AML, AML with myelodysplasia-related changes (AML-MRC), and therapy-related acute myeloid leukemia (tAML)), and identified differences in mutation types, spectrum, and hotspots between disease categories and compared to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC compared to MDS. TP53 mutations in MDS were more likely to retain transcriptional activity, and co-mutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutated TP53 contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification of TP53 mutations in myeloid malignancies. Statement of SignificanceThe distribution and functional consequences of TP53 mutations differ between hematologic malignancies and solid tumors, and, among myeloid neoplasms, between myelodysplastic syndrome and acute leukemia. These findings suggest distinct biological mechanisms for mutated p53 in hematologic malignancies, specifically in initiation and progression of myeloid neoplasia, that warrant further investigation.